Open AccessKinase‐Deficient Forms of Jak1 and Tyk2 Inhibit Interferon α Signaling in a Dominant Manner
Author(s) -
Krishnan Kartik,
Pine Richard,
Krolewski John J.
Publication year - 1997
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1997.00298.x
Subject(s) - janus kinase , kinase , tyrosine kinase 2 , phosphorylation , jak stat signaling pathway , microbiology and biotechnology , biology , tyrosine kinase , janus kinase 1 , tyrosine phosphorylation , receptor tyrosine kinase , signal transduction , cancer research , biochemistry , receptor , platelet derived growth factor receptor , growth factor
Signaling by interferon α (IFNα), an extracellular factor that mediates a number of anti‐viral and growth‐suppressive effects, requires two members of the Janus family of tyrosine kinases (JAK family): Jak1 and Tyk2. IFNα treatment of cells induces the rapid tyrosine phosphorylation of these two kinases, two subunits of the IFNα receptor, and two members of the signal transducer and activator of transcription (STAT) family of latent transcription factors. These proteins are believed to be direct substrates of one or both JAKs. Though the requirement for both Jak1 and Tyk2 in the IFNα‐signaling cascade is well established, the order of activation and the relative contribution of the two kinases has not been elucidated completely. To address these questions, we have employed kinase‐deficient mutants of both enzymes. Both mutant kinases suppress transcriptional activation as measured by an IFNα‐dependent reporter‐gene assay. Furthermore, in transient‐transfection assays, the kinase‐deficient versions of Tyk2 and Jak1 can act independently to inhibit STAT phosphorylation. Thus, kinase‐deficient versions of JAK can act in a dominant‐negative fashion to suppress IFNα signaling. The effects of the overexpressed mutant kinases on the phosphorylation of the kinases themselves, however, are unequal, suggesting that Jak1 functions upstream of Tyk2.